Animal models of alcohol withdrawal.

One diagnostic criterion of alcohol dependence is the appearance of a withdrawal syndrome when alcohol consumption ceases. Researchers have used various animal models, including isolated brain cells, slices of brain tissue, and intact animals, to study the mechanisms and manifestations of withdrawal. Results from these experimental studies have demonstrated that many consequences of withdrawal found in animals resemble those observed in humans. Such signs and symptoms of alcohol withdrawal include enhanced activity of the autonomic nervous system; body posture and motor abnormalities; hyperexcitability of the central nervous system, including sensory hyperreactivity; convulsions; anxiety; and psychological discomfort. Researchers also have used animal models to study the electrophysiological correlates of withdrawal, as well as neurobiological mechanisms underlying alcohol dependence and withdrawal.

xc e s s i ve alcohol consumption over a prolonged period of time results in alcohol dependence, a m a l a d a p t i ve neurophysiological state that leads to a constellation of clinical signs and symptoms 1 (i.e., alcohol withdrawal syndrome) when alcohol consumption is reduced drastically or stopped completely. These signs and symptoms typically reflect compensatory responses thought to re p resent the brain's attempt to re-establish a functional balance (i.e., homeostasis) during continuous alcohol exposure (Becker 1999;Littleton 1998;Metten and Cr a b b e 1996). Consequently, these re s p o n s e s a re the opposite of alcohol's depre s s a n t effects on brain function. The clinical f e a t u res of alcohol withdrawal generally fall into three categories: (1) hyperactivi t y of the autonomic nervous system, which regulates vital functions, such as h e a rt rate, blood pre s s u re, and re s p i r ation; (2) hypere xcitability of the central n e rvous system (CNS); and (3) distor-tions in sensation and perception (e.g., Anton and Becker 1995;Saitz 1998) (see table 1).
Each withdrawal sign and symptom usually emerges at a specific period foll owing the reduction or cessation of alcohol consumption. In other word s , withdrawal signs and symptoms follow a distinct temporal pattern. For example, tremors, anxiety, sleeplessness, re s tlessness, and nausea can begin as early as 6 hours after intoxication declines. Se i z u res usually occur within 48 hours after cessation of drinking, where a s delirium tremens (DTs) develop 1 to 4 days after the onset of acute alcohol withdrawal. The severity of withdrawalrelated sequelae varies along a continuum, ranging from re l a t i vely mild symptoms after a single heavy drinking epsode (often re f e r red to as a "hangove r") to m o re serious and complicated withdrawal symptoms resulting from chronic alcohol e x p o s u re. Overall, extensive va r i a b i l i t y exists among alcoholics with respect to the incidence and intensity of withdrawal signs and symptoms. This va r iability is undoubtedly related to a host of factors, such as amount, duration, and pattern of alcohol use; simultaneous abuse of drugs other than alcohol; c o m p romised nutritional status; and coexisting illnesses (Saitz 1998). These factors, in turn, are influenced, to va rying extents, by genetic forces.

HOWA R D C. BE C K E R, PH. D . , is a pro f e ssor in the departments of psyc h i a t ry and b e h a v i o ral sciences and of physiology and n e u roscience at the Medical Un i versity of South Ca rolina and is a re s e a rc h c a reer scientist at the De p a rtment of
Ve t e rans Affairs Medical Ce n t e r, C h a rleston, South Ca ro l i n a .
Because of the diverse aspects of alcohol withdrawal and the countless i n t e rvening and confounding va r i a b l e s that may influence the syndro m e's manifestation, clinicians have difficulty in identifying risk factors, vulnerability, and underlying mechanisms of withdrawal in clinical studies of human alcoholics. The use of animal models to study alcohol dependence and withdrawal has enabled re s e a rchers to cont rol both genetic and enviro n m e n t a l factors contributing to alcohol withdrawal. Such studies have been critical in advancing knowledge about etiological factors and pathophysiological pro c e s s e s associated with alcohol withdrawal. This article re v i ews the experimental strategies used in animal models and describes the withdrawal signs and symptoms observed in such models.

Experimental Strategies and Methods for Chronic Alcohol Exposure
Animal models have been extre m e l y useful for investigating the factors that influence both risk and severity of alcohol withdrawal. These studies have employe d a number of mammalian species, including c h i m p a n zees and monkeys, dogs, cats, and rodents. Studies seeking to identify the biological, or intrinsic, influences (e.g., genetic pre d i s p o s i t i o n , age, and gender) and environmental, or extrinsic, influences on alcohol dependence and withdrawal have primarily used ro d e n t s .
Two types of experimental strategies h a ve demonstrated the importance of a genetic predisposition in shaping withdrawal symptoms. For the first strategy, those animals within one strain that s h ow a particularly high or low pro p e n s i t y for alcohol withdrawal are selective l y b red over several generations to generate two lines (i.e., selected lines) that differ only in their susceptibility to withdrawal, but not in the rest of their genetic makeup (i.e., genotype). The second approach invo l ves comparing the susceptibility to withdrawal symptoms in numerous unrelated inbre d animal strains with different genotypes. Other studies have identified a d d i t i o n a l biological variables that influence a l c ohol withdrawal. For example, experiments suggesting potential roles for c e rtain hormones (e.g., steroid hormones that affect nerve cell function) h a ve indicated that gender plays a ro l e . Fu rt h e r m o re, investigations demonstrating developmental differences in n e u roplasticity-that is, in the brain's ability to adapt to changes in the enviro n m e n t -f o l l owing chronic alcohol e x p o s u re have re vealed the influence of age on susceptibility to withdrawal.
Re s e a rchers have evaluated the influence of environmental factors in animal studies in which inve s t i g a t o r s h a ve systematically manipulated the a n i m a l s' alcohol exposure while otherwise controlling other enviro n m e n t a l and biological influences. These studies h a ve firmly established the modulating effects of alcohol dose (i.e., the amount consumed), duration of exposure, and pattern of exposure (i.e., the history of p revious withdrawal experiences) on various parameters of the withdrawal s y n d rome. These findings have laid the foundation for using these models in expanding investigations on underlying mechanisms of withdrawal as well as for assessing the efficacy of va r i o u s pharmacological treatment strategies for alcohol withdrawal.
To investigate the consequences of c h ronic alcohol exposure and withdrawal, re s e a rchers have conducted their studies both in the "test tube" (i.e., in vitro ) and in intact animals (i.e., in vivo ) . Both of these approaches are discussed in the following paragraphs.

In Vitro Models
With in vitro models, embryonic or neonatal nerve cells (i.e., neuro n s ) extracted from various brain regions of rats or mice typically are grown and maintained in an artificial enviro n m e n t designed to simulate physiological conditions. To study the effects of alcohol e x p o s u re or withdrawal, alcohol is added to or re m oved from the fluid that supports and sustains the cells' viability (i.e., the culture medium) ( Hu and Ticku 1997). The adva n t a g e of these models is that the inve s t i g a t o r s can accurately control the dose and duration of alcohol exposure and determine alcohol's direct effects on n e u ronal function under conditions that minimize extraneous influences. Such isolated systems also can be a d i s a d vantage, howe ve r, because they p reclude the analysis of potential complex interactions among different cells and brain regions that contribute to a l c o h o l's effects.
A l t e r n a t i ve l y, re s e a rchers have examined the effects of chronic alcohol e x p o s u re in thin slices of brain tissue that pre s e rve the integrity of at least some of the cellular arc h i t e c t u re and connections (i.e., synapses) of the tissue. In these studies, one can either t reat the intact animal with alcohol and then extract and examine the brain slices or one can first extract the tissue slices and then treat them with alcohol once they are being cultured (Bailey et al. 1998;Thomas et al. 1998).
C o l l e c t i ve l y, these in vitro models h a ve been used to study cellular and molecular events associated with c h ronic alcohol exposure and withdrawal. Although these techniques are well suited for mechanistic inve s t i g ations (e.g., of the electro p h y s i o l o g i c a l , biochemical, and molecular mechanisms contributing to withdrawal), the full spectrum of withdrawal symptoms and associated events (including behavioral and physiological measures) can best be studied in intact animals.

In Vivo Models
A variety of in vivo models have been used to study the effects of chro n i c alcohol exposure and withdrawal. In these studies, alcohol administration is a c h i e ved through three main techniques, as follow s : • Because many animals do not vo luntarily consume large (and consis-tent) alcohol amounts, alcohol administration often is forc e d -t h a t is, imposed and controlled by the i n ve s t i g a t o r. For example, the alcohol may be delive red directly to the stomach by intragastric infusion, or the animal may be continuously exposed to alcohol vapor in an inhalation chamber. Both of these strategies provide the experimenter with a great deal of control over critical variables of alcohol exposure , such as dose and timing (i.e., initiation, duration, and termination of e x p o s u re ) .
• For a less controlled approach, alcohol can be provided with the diet, most commonly as part of a nutritionally balanced liquid diet that constitutes the animals' sole sourc e of food and fluid. Under these conditions, animals typically consume sufficient quantities of alcohol to a c h i e ve dependence as evidenced by the emergence of withdrawal symptoms when the alcohol is omitted f rom the diet. With this appro a c h , the investigator controls the duration of exposure, but the animal determines the dose and pattern of alcohol consumption.
• The third strategy relies on vo l u nt a ry alcohol consumption. These models usually entail the use of animals that are genetically pre d i s p o s e d to high alcohol pre f e rence and drinki n g behavior when given a choice b e t ween alcohol and water.
With all of these strategies, re s e a rc h e r s can achieve sustained alcohol exposure (i.e., persistent alcohol levels in the blood and brain) that results in the deve l o p m e n t of withdrawal signs and symptoms once alcohol administration is terminated. As with humans, withdrawal signs and symptoms in the animals wax as blood and brain alcohol levels dro p, peak a round the time when alcohol is completely eliminated from the body, and wane over the course of several days. Nu m e rous variables influence the seve ri t y and timing of various components of the withdrawal syndrome in each animal, including the amount, duration, and pattern of alcohol exposure prior to withdrawal (Becker et al. 1997;Goldstein 1972;Macey et al. 1996;Watson and Little 1995).
Scientists also have developed seve r a l animal models to examine the consequences of repeated withdrawal experiences. In general, these studies have c o r roborated clinical findings obtained in humans indicating that people with a history of multiple detox i f i c a t i o n s experience more seve re and medically complicated withdrawal than do people experiencing their first withdrawal episode. This pro g re s s i ve intensification of withdrawal signs and symptoms may reflect a "kindling" or sensitization phenomenon. Tr a d i t i o n a l l y, kindling refers to a process in which a weak electrical or chemical stimulus that initially causes no ove rt behavioral re s p o n s e s comes to result in behavioral effects (e.g., seizures) when administered re p e a te d l y. The mechanisms underlying such a potential sensitization re g a rding withdrawal, howe ve r, remain unclear and a re currently being investigated (Be c k e r 1998, 1999; Becker and Littleton 1996).

Withdrawal Signs and Symptoms in Animal Models
Nu m e rous animal models invo l v i n g d i verse methods of alcohol exposure h a ve identified a plethora of behavioral and physiological measures of withdrawal that to a great extent correspond to the withdrawal signs and symptoms o b s e rved in humans (see table 2) (for re v i ews, see Deitrich et al. 1996;Fi n n and Crabbe 1997;Friedman 1980;Metten and Crabbe 1996). The follow i n g sections re v i ew some of these findings.

Enhanced Autonomic Activation
The autonomic nervous system has two p a rts. One part is the sympathetic nervous system, which accelerates the heart rate, constricts the blood vessels, a n d i n c reases blood pre s s u re. The second p a rt is the parasympathetic nervous system, which slows the heart rate, increases the activity of the gastrointestinal (GI) tract and the glands, and re l a xes certain muscles (i.e., sphincters) in the GI tract.
During alcohol withdrawal, the activity of the autonomic nervous system shifts to favor sympathetic activity (e.g., Hawley et al. 1994;King et al. 1994). As a result, laboratory animals undergoing withdrawal experience changes in c a rd i ovascular functions (e.g., eleva t e d h e a rt rate and blood pre s s u re) and GI functions (e.g., reduced food and water intake and diarrhea) (Crandall et al. 1989;Friedman 1980) similar to the effects observed in humans. Alcohol withdrawal, as well as alcohol exposure, also causes alterations in the animals' ability to regulate body temperature. Fi n a l l y, animals undergoing alcohol withdrawal exhibit tremors and piloerection (i.e., body hair standing up, which in humans results in "goose bumps" ) ( Friedman 1980;Frye et al. 1983).

Body Posture and Motor Abnormalities
Rodents undergoing alcohol withdrawal demonstrate numerous indicators of i m p a i red body function and motor a c t i v i t y. For example, in rats, tail stiffness is a characteristic feature of alcohol withdrawal. In addition, re s e a rchers have o b s e rved muscle spasms and abnormalities in body posture (i.e., rigidity) (see Friedman 1980) as well as alterations in gait and locomotor behavior ranging f rom depressed activity to wild fits of u n c o n t rolled running. Fu rt h e r m o re , mice undergoing alcohol withdrawal exhibit various stereotypic behaviors, including backward walking and wall climbing (e.g., Becker et al. 1987). To m e a s u re these general withdrawalrelated events, an investigator typically o b s e rves the animals during withdrawal and re c o rds abnormalities using a scoring schema. Because the assignment of s c o res using this approach is somew h a t s u b j e c t i ve, it is critical that the observe r be unaware of the animals' experimental histories (i.e., whether they we re a l c o h o l -t reated or control animals) in o rder to minimize experimental bias.

Sensory Hyperreactivity
Studies in human alcoholics have re ve a l e d a heightened reactivity to enviro n m e ntal stimuli during detoxification (e.g., Grillon et al. 1994;Krystal et al. 1997).
To model this enhanced re a c t i v i t y, re s e a rchers have exposed animals to various sensory stimuli. For example, studies measuring the animals' start l e response to auditory or tactile stimuli, such as an air puff, noted enhanced re s p o n s i veness during withdrawal (Ma c e y et Po h o recky et al. 1986;Rassnick et al. 1992). Hy p e r re a c t i v i t y during withdrawal also occurs in re s p o n s e to ave r s i ve stimuli, such as mild elect roshocks. Fi n a l l y, animals undergoing withdrawal commonly exhibit enhanced sensitivity to pain (i.e., hyperalgesia), for example, after the application of a heat stimulus to the tail or a paw (e.g., Gatch and Lal 1999).

Convulsions
A hallmark feature of alcohol withdrawal is enhanced susceptibility to seizure s (e.g., Becker 1999; Finn and Cr a b b e 1997; Victor 1970). Because it is re l at i vely simple to identify, measure, and quantify the severity of seizures, this aspect of withdrawal has been studied e x t e n s i vely in animal models. These analyses have included both spontaneous and experimentally induced convulsions. To elicit seizures in animals undergoing withdrawal, re s e a rchers have used n u m e rous pro c e d u res, as follows (for re v i ews, see Deitrich et al. 1996; Fr i e d m a n 1980; Metten and Crabbe 1996): • Ex p o s u re to a sensory stimulus, commonly a sound (i.e., an audiogenic stimulus) • Handling the animal, for example, lifting it by the tail; with this a p p roach, which is commonly used in mouse studies of alcohol withdrawal, the convulsions are score d depending on the degree of manipulation re q u i red to induce the re s p o n s e • Ex p o s u re to mild electric stimuli, either to larger body areas (e.g., elec-t ro c o n v u l s i ve stimulation) or to disc rete brain regions (e.g., in the cortex or in subcortical brain are a s ) • Administration of chemical substances (i.e., chemoconvulsants), either to the general bloodstream or d i rectly to specific brain re g i o n s .
The convulsive behaviors elicited by these various experimental pro c e d u re s during alcohol withdrawal appear to reflect a general state of heightened CNS e xc i t a b i l i t y. (The electrographic correlates of this hypere xcitability are described in the sidebar, pp. 141-143.) For examp l e , studies have found that in animals undergoing withdrawal, both the thre s ho l d amount (e.g., the current used for electrical stimuli or the dose of chemical stimuli) and the number of subthre s h o l d stimulations re q u i red to elicit a convulsion we re reduced compared with contro l animals (Deitrich et al. 1996; Fr i e d m a n 1980; Metten and Crabbe 1996). Fu rt h e r m o re, in all cases the severity of the convulsive responses varied in a manner that presumably reflects the intensity of withdrawal-related CNS h y p e re xc i t a b i l i t y. In t e re s t i n g l y, the timing for the expression of spontaneous and various experimentally induced convulsions during withdrawal differe d , suggesting that different neural mechanisms underlie heightened CNS e xcitability at different times during the course of withdrawal (Go n z a l ez et Watson and Little 1995).
C o n v u l s i ve responses elicited during alcohol withdrawal are similar to those elicited during withdrawal from other CNS depressants (e.g., barbiturates and b e n zo d i a zepines). Fu rt h e r m o re, the convulsions associated with alcohol withdrawal may be exacerbated by drugs that p romote convulsions and ameliorated by anticonvulsant drug treatment (e.g., Anton and Becker 1995). Consequently, these animal models of withdrawalassociated seizures have been pivotal in p roviding information about the conditions under which CNS hypere xcitability may be behaviorally expre s s e d . Mo re ove r, these models h a ve offere d insights into underlying mechanisms and effective treatment strategies for this potentially life-threatening aspect of alcohol withdrawal.  , File et al. 1992;Koob and Britton 1996).

Anxiety
Another model used to study withd r a w a l -related anxiety invo l ves the d rug discrimination paradigm. In this p ro c e d u re animals are trained to discriminate between the subjective cues (i.e., "f e e l i n g s") associated with an anxiogenic compound (e.g., pentylenetetr a zole [PTZ]) and an inactive compound (i.e., a placebo). The animals are show n two levers and re c e i ve a rew a rd (i.e., are re i n f o rced) for responding by pre s s i n g one lever following PTZ administration (i.e., when they are feeling "a n x i o u s" ) and the other lever following placebo administration (i.e., when they are feeli n g "n o r m a l"). Discrimination learning i s c o n s i d e red successful when the animals p redominantly respond on the appropriate levers following PTZ or placebo H y p e re xcitability of the central nervous system (CNS) is an important feature of alcohol withdrawal. This hypere xcitability can be analyze d not only through behavioral measures, such as convulsions, but also through electrophysiological changes in brain activity. One approach to measuring electro p h y s i ological changes is an electroencephalogram (EEG). An EEG re c o rds the combined activity of large ensembles of n e rve cells (i.e., neurons) by tracing the electric potential (i.e., voltage) produced by those cells. EEGs show neuro n activity as characteristic fluctuations in voltage (i.e., brain w a ves) that are detected by electrodes placed on the outside of the head, directly on the brain, or within the brain tissue. Characteristic changes in the brain waves, such as their size, amplitude, or fre q u e n c y, may indicate cert a i n p s ychological states, levels of consciousness, and neurological disorders.
Pe rturbations in neural activity cause either changes in spontaneous EEG activity or changes in response to the presentation of external stimuli, called evoked or e ve n t -related potentials (ERPs). Analyses of spontaneous EEG activity focus on changes in ongoing brain activity over time. Conve r s e l y, ERPs provide information about an individual's ability to process and respond to sensory stimuli. For example, re s e a rchers can determine the time b e t ween the presentation of the stimulus and the appearance of the ERP. This is called the latency of the ERP. Computer-assisted analytic techniques also allow re s e a rchers to determine the frequencies of the pre d o m inant wave forms and to detect brain wave abnormalities that appear as greater-than-normal spikes and sharp w a ves (i.e., epileptiform activity)(see figure). Although the pro c e d u res for assessing spontaneous EEG activity and ERPs are distinct, the measures provide complement a ry information about the functional integrity of intact neural circ u i t s .
EEG analyses have been useful in studying neurophysiological effects of acute and chronic alcohol expos u re, which results in well-documented changes in spontaneous EEG activity, ERPs, and epileptiform activity in both humans and animal models (e.g., Porjesz and Begleiter 1996). During acute withdrawal after chro n i c alcohol consumption, alcoholics exhibit abnormalities in both spontaneous EEG activity and ERPs, as follow s : • Spontaneous EEG activity shows shifts in the predominant wave form frequencies and changes in the magnitude of the EEG signals within the differe n t f requency bands.
• ERP alterations include increased amplitudes and d e c reased latencies.
C o l l e c t i ve l y, these neurophysiological changes suggest a rebound CNS hypere xcitability-that is, once alcohol with its depressant effects on brain activity is eliminated, the brain responds with greater-than-normal exc i t a b i l i t y (e.g., Biggins et al. 1995;Emmerson et al. 1987;Kaplan et al. 1985;Kathmann et al. 1996). Although some of

Electrophysiological Indices of Withdrawal-Related CNS Hyperexcitability
Sample electroencephalogram (EEG) recorded from a rat following alcohol withdrawal. Filled circles indicate computer-detected spikes and sharp waves, which are indicators of abnormal brain activity. Animal Models of Alcohol Withdrawl these alterations in spontaneous EEG activity and ERPs dissipate with prolonged abstinence, other abnormalities persist (Porjesz and Begleiter 1996). Many of the EEG abnormalities also have been demonstrated in various animal models of alcohol withdrawal, including mice (Walker and Zo r n e t zer 1974), rats (Ehlers and Chaplin 1991; Po l d rugo and Sn e a d 1984), cats (Perrin et al. 1975), and primates (Eh l e r s 1988). Indeed, studies using animal models have not only served to substantiate clinical findings, but have p rovided additional insight into subcortical epileptiform activity that may underlie and precede the convulsions associated with alcohol withdrawal. For example, the magnitude and frequency of epileptiform activity differs among various brain regions, with subcortical stru c t u re s (especially hippocampus and amygdala 1 ) exhibiting higher levels of spike activity than the cortex. Mo re ove r, in rodent models, various regions of the hippocampus differ in their EEG response to chronic alcohol exposure and withdrawal. That is, the response of some hippocampal regions is influenced by the amount of alcohol e x p o s u re prior to withdrawal, whereas EEG abnormalities in other hippocampal regions are influenced more by the number of prior withdrawal episodes (Veatch and Go n z a l ez 1996). Fi n a l l y, using various experimental a p p roaches that invo l ve in vivo and in vitro re c o rd i n g techniques, re s e a rchers are beginning to elucidate the biochemical mechanisms underlying these neuro p h y s i ological indices of withdrawal-related CNS hypere xc i t a b i lity (e.g., Thomas et al. 1998;Whittington et al. 1995). administration. Animals undergoing alcohol withdrawal generally press the PTZ leve r, even though they have not re c e i ved the agent. This observa t i o n suggests that for the animals, the subject i ve experience of alcohol withdrawal is similar to that associated with PTZ administration (Gauvin et al. 1992;Lal et al. 1988). Agents that effectively alleviate anxiety during alcohol withdrawal can block this generalization-that is, animals receiving those agents no longer p ress the PTZ lever during withdrawal (Lal et al. 1988). Other studies have demonstrated that animals can clearly discriminate the subjective effects associated with alcohol intoxication (i.e., a " h a n g ove r") and the subjective aspects of acute alcohol withdrawal (Gauvin et al. 1993).
The application of these va r i o u s behavioral models of withdrawalassociated anxiety has played a key ro l e in characterizing the anxiogenic compon e n t of the withdrawal syndrome, as we l l as in identifying conditions that maxim i ze its expression. This work also has been instrumental in providing insight into underlying neurobiological mechanisms and into manipulations that may alleviate withdrawal-related anxiety.

Psychological Discomfort
The most challenging aspect of studying alcohol withdrawal models in animals has been the associated psychological disc o m f o rt (e.g., distress and depre s s i o n ) . Animals undergoing alcohol withdrawal h a ve been noted to exhibit "irritability" and "a g g re s s i ve n e s s"; howe ve r, these behaviors are subjective effects that are difficult to manipulate experimentally. One behavioral measure that has been postulated to reflect the stressful nature of withdrawal is the emission of sounds at ultrahigh frequencies (i.e., ultrasonic vocalizations) in rodents. These "d i s t re s s" sounds increase dramatically in animals experiencing withdrawal, an effect that can be lessened by the administration of antianxiety drugs (Knapp et al. 1998).
One common characteristic of withd r a w a l -related discomfort is a re d u c e d ability to derive pleasure from naturally rew a rding events (i.e., anhedonia).
Re s e a rchers have studied this subjective quality of alcohol withdrawal by assessing threshold levels for the perc e p t i o n of rew a rding stimuli. In these experiments, animals are first trained to perform a task (e.g., press a lever) to re c e i ve a mild electric stimulus delive red to a site within the brain's "rew a rd center. " By systematically manipulating the stimulus intensity, the investigators can establish a threshold level of electrical stimulation that is perc e i ved by the animal as being rew a rding-that is, the c u r rent at which the animal re s p o n d s for another stimulation 50 percent of the time. Such experiments found that alcohol initially lowers that rew a rd t h reshold, because a weaker current is sufficient for the animal to perc e i ve the stimulus as being rew a rding. Du r i n g alcohol withdrawal, howe ve r, the thre s ho l d for brain rew a rd stimulation is significantly elevated (Schulteis et al. 1995). This model allows re s e a rchers to eva l uate subtle ave r s i ve qualities of alcohol withdrawal that may contribute, at least in part, to the motivation for re s u m i n g drinking (i.e., relapse).

Summary
Alcohol withdrawal syndrome comprises n u m e rous signs and symptoms that emerge following cessation of drinking in people who exc e s s i vely consume alcohol over a prolonged period of time. Many of these withdrawal signs and symptoms have been explored using both in vitro and in vivo animal models. Both of these re s e a rch approaches have a d vantages and disadvantages, depending on whether one wants to study specific mechanisms underlying withdrawal or more general physiological and behavioral aspects of the synd rome. For example, in vitro models a l l ow greater c o n t rol over the experimental conditions and facilitate analyses of withdrawal-related processes at the cellular level. Alternative l y, in vivo models enable re s e a rchers to inve s t i g a t e the effects of alcohol exposure and withdrawal on the e n t i re organism. Such investigations facilitate analyses of behavioral and physiological c o n s e-quences of withdrawal and allow re s e a rchers to evaluate the effective n e s s of various treatment strategies.
Using a variety of model systems and alcohol administration pro t o c o l s , re s e a rchers have been able to demons t r a t e many of the withdrawal signs and symptoms observed in humans. These studies have provided valuable insights into the etiology and underlying mechanisms of numerous withdrawal-re l a t e d e vents, including enhanced autonomic n e rvous system activation, sensory h y p e r re a c t i v i t y, convulsions, anxiety, and dysphoria. Based on these findings, re s e a rchers and clinicians hope to gain a better understanding of the sequelae of alcohol withdrawal, as well as deve l o p n ovel and more effective tre a t m e n t strategies for ameliorating those sequelae, there by improving the chances of alcoholics to achieve abstinence. s